Lipopolysaccharide (LPS) is the major structural component of gram negative bacteria and is composed of three distinct domains; lipid A, a core oligosaccharide chain, and an O-antigen. Of the three LPS domains discussed, the O-antigen is most variable and distinguishes among various gram negative bacterial strains. Importantly, LPS is recognized by the immune system during infection. It is this recognition and interaction between LPS and the immune system, specifically the innate branch of the immune system, which leads to a potentially life threatening condition known as sepsis. Septic shock remains the number one cause of death in intensive care units and is responsible for 750,000 new cases with 250,000 of these new cases resulting in death within the U.S. Death by septic shock is attributed to the inflammatory cytokines released by members of the innate immune system, such as antigen presenting cells (APC), which ultimately leads to dysfunction and failure of the body's major organ systems.
Inflammatory cytokine secretion occurs upon the initial interaction between LPS and its receptor, toll-like receptor 4 (TLR-4), present on antigen presenting cells (APCs) such as macrophages and dendritic cells. TLR-4 belongs to a family of transmembrane receptors, which are responsible for recognizing and responding to pathogen associated molecular patterns (P AMPS) such as LPS. Upon activation of TLR-4, a series of signal transduction events occur ultimately leading to nuclear translocation of transcription factor NF-KB, subsequently resulting in transcription of various inflammatory cytokines such as TNF-α, IL-1β, and IL-12p70. Collectively, these inflammatory cytokines are responsible for the systemic inflammatory response syndrome observed during septic shock. Although responsible for causing systemic inflammation, the inflammatory response associated with LPS may be beneficial if the signal transduction initiated by LPS, which is similar to that observed in adjuvants, can be optimally regulated.
Adjuvants are substances that accelerate and/or enhance an antigen specific immune response. The purpose of an adjuvant is to make an antigen visible to the eyes (macrophages/dendritic cells) of the immune system. Recognition of antigens by APCs essentially initiates the critical cascade of events leading to localized inflammation, which recruits APCs and ultimately leads to initiation of a productive cell mediated and/or antibody mediated immune response. Although various adjuvants exist, not all are approved for human use and the adjuvants which are approved are associated with adverse side effects such as malaise and inflammation. Currently, the majority of human vaccines contain aluminum salts as an adjuvant and pharmaceutical companies are developing oil-based adjuvants to be incorporated into vaccines. Another class of adjuvants which is gaining interest is toll-like receptor (TLR) agonists. Currently, adjuvants which act as agonists to TLR-2, TLR-5, TLR7/8, and TLR-9 are being studied, and one TLR-4 agonist, monophosphoryl lipid A, is FDA approved. Although promising, many of these agonists are bacterial molecules.